Closed-Loop Delivery Systems for Insulin Therapy

Brunetti, P; Benedetti, M. Massi; Calabrese, Giuseppe; Reboldi, Gianpaolo

doi:10.1177/039139889101400404

Cited by 6 publications

(2 citation statements)

References 56 publications

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“…Considerable effort has gone into developing indwelling sensors that provide feedback control of closed-loop therapies-for example, the glucose sensor of the artificial pancreas. [1][2][3][4] Although several studies have discussed glucose sensors which successfully functioned for several weeks in vivo, no sensor appears capable of reliably surviving long-term subcutaneous implantation, most likely owing to consequences of the foreign-body response. 5 There are many implications in the literature that the mature fibrous capsule (FC) that forms around implanted sensors retards the transport of even low-molecular-weight analytes such as glucose to the sensor surface [6][7][8][9][10][11][12] and can be reviewed in Reichert and Sharkawy.…”

Section: Introductionmentioning

confidence: 99%

Engineering the tissue which encapsulates subcutaneous implants. I. Diffusion properties

Sharkawy

Klitzman

Truskey

et al. 1997

J. Biomed. Mater. Res.

128

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This report uses normal rat subcutis as a reference point to provide a quantitative analysis of small analyte transport through the tissue which encapsulates implants. Polyvinyl alcohol (PVA) with 60-and 350-m mean pore size (PVA-60, PVA-350), nonporous PVA (PVA-skin), and stainless-steel cage (SS) specimens were implanted in the subcutis of Sprague-Dawley rats for 4 weeks to elicit a range of capsular wound-healing tissues. Histologic examination showed that the capsular tissue which formed around PVAskin and SS specimens was densely fibrous and avascular. That forming around PVA-60 and PVA-350 was less densely fibrous and more vascular. The fibrous content of capsular tissue and subcutis was determined from eosin-stained histologic sections. Dual-chamber diffusion measurements of sodium fluorescein (M w 376 g/mol) through capsular tissue and normal rat subcutis were used to quantitatively compare the effective diffusion coefficients of small analytes on the order of glucose. The two most fibrous capsular tissues exhibited diffusion coefficients that were statistically (p < 0.05) less than that determined for rat subcutis by 50 and 25% for PVA-skin and SS, respectively. The diffusion coefficients of the less dense capsular tissue which formed around the porous implants were not statistically different from subcutis. The experimentally measured diffusion coef-ficients of the two most fibrous capsular tissues were closely predicted by a simple two-component diffusion model consisting of an aqueous interstitium with an array of impenetrable bodies equal in volume fraction to the fibrous content of the tissue. This model overestimates the diffusion coefficients measured for the least fibrous tissues. Using the diffusion coefficient measured for the PVA-skin capsular tissue, a finite difference model predicts that a 200-m-thick capsular layer would increase from 5 to 20 min the time required for subcutaneously implanted sensor to detect 95% of the blood analyte concentration. This study suggests that the fibrous capsule forming around a subcutaneously implanted smooth-surface sensor imposes a significant diffusion barrier to small analytes such as glucose, thus increasing the lag time of the sensor by as much as threefold. A corollary observation is that a sensor with a porous surface which allows tissue ingrowth may be more responsive to blood analyte fluctuations as a result of its a more vascular and less fibrous encapsulation tissue.

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Section: Introductionmentioning

confidence: 99%

Engineering the tissue which encapsulates subcutaneous implants. I. Diffusion properties

Sharkawy

Klitzman

Truskey

et al. 1997

J. Biomed. Mater. Res.

128

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“…Hence, many investigations have been dedicated to develop environmentally responsive delivery systems . Commonly, a glucose-responsive insulin delivery system (GRIDS) is able to sense the increased glucose concentration and subsequently release the required amount of insulin according to the glucose level. − GRIDS may not only replace the recurrent insulin injections, but can also reduce the patient’s direct involvement in glucose control and prevent insulin from excessive or insufficient dosage. ,,− One approach used for sensing glucose is to incorporate a glucose-responsive element such as glucose oxidase (GOx) into the delivery system, whereby GOx catalyzes the conversion of d -glucose into gluconic acid to reduce the local pH. − The acidic pH subsequently results in the conformational or structural changes of the carrier and ultimately releases the insulin. ,,, Such a strategy has been notably employed in pH-responsive hydrogels. ,− …”

mentioning

confidence: 99%

Glucose-Responsive Peptide Coacervates with High Encapsulation Efficiency for Controlled Release of Insulin

2018

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A new glucose-responsive insulin delivery system is fabricated using biomimetic peptide coacervates derived from the Humboldt squid (Dosidicus Gigas) beak. Both insulin and glucose oxidase are coencapsulated within coacervate microdroplets. The glucose oxidase quickly responds to increasing glucose levels to generate a local acidic environment, thereby rapidly triggering the dissociation of pH-sensitive coacervates to release the insulin cargo. The rate of insulin release is dependent on the glucose level, increases under hyperglycemic conditions, and decreases under normoglycemic conditions. This glucose responsiveness mimics pancreatic β-cell function by releasing insulin according to glucose levels.

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